Cancer is a broad group of diseases involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invading nearby parts of the body. The cancer may also spread to more distant parts of the body through the lymphatic system or bloodstream. There are over 200 different known cancers that affect humans. Whereas good treatment options are available for many cancer types, others still represent unmet medical needs. In particular, ovarian cancer, renal cell carcinoma, and triple negative breast cancer (TNBC) are malignancies with limited therapeutic options. TNBC is an aggressive subtype of breast cancer associated with high risk of metastasis and early relapse. Currently the main option for systemic therapy of TNBC patients is chemotherapy with an overall poor efficacy and severe side effects. Initially, the majority of TNBC patients respond to neoadjuvant chemotherapy treatment, but only about 20% reach a pathological complete response (pCR) with good prognosis. Notably, most patients do not reach pCR because tumors either have lower de novo sensitivity to chemotherapy or develop resistance to chemotherapy. In such cases, tumors regress due to chemotherapy, but residual cancer cells persist and initiate tumor recurrence and metastasis within three years after chemotherapy in about 40% of patients.
Sialyl-glycolipid stage-specific embryonic antigen 4 (SSEA4) is a sialyl-glycolipid epitope also known as monosialosyl globopentaosylceramide (MSGb5), initially identified on human teratocarcinoma cells (Kannagi R et al., EMBO J. 1983; 2(12):2355-61; Saito S et al., J Biol Chem. 2003 Jul. 18; 278(29):26474-9). SSEA4 is found on undifferentiated human embryonic stem (ES) cells, induced pluripotent (iPS) cells, embryonal carcinoma (EC) cells, and embryonic germ (EG) cells and a variety of somatic stem cells, such as dental pulp stem cells, umbilical cord blood-derived very small embryonic like stem cells (VSELs) and mesenchymal stromal cells (Gang E J et al., Blood. 2007 Feb. 15; 109(4):1743-51; Truong T T et al., Invest Ophthalmol Vis Sci. 2011 Aug. 11; 52(9):6315-20).
In EP14305477.3 it is disclosed that SSEA4 is a biomarker to mark a subpopulation of chemotherapy resistant cancer cells.
The function of SSEA4 is still unknown.
The chimeric antigen receptor (CAR) provides a promising approach for adoptive cell immunotherapy for cancer. Commonly, CARs comprise a single chain fragment variable (scFv) of an antibody specific for a tumor associated antigen (TAA) coupled via hinge and transmembrane regions to cytoplasmic domains of T-cell signaling molecules. The most common lymphocyte activation moieties include a T-cell costimulatory (e.g. CD28, CD137, OX40, ICOS, and CD27) domain in tandem with a T-cell triggering (e.g. CD3ζ) moiety. The CAR-mediated adoptive immunotherapy allows CAR-grafted cells to directly recognize the TAAs on target tumor cells in a non-HLA-restricted manner.
Although less than 25% of breast cancer patients benefit from chemotherapeutic treatment (CLIFFORD A. HUDIS and LUCA GIANNI, The Oncologist 2011; 16 (suppl 1):1-11), this systemic approach is still used as standard care. Because of the severe side effects, it would be highly beneficial to identify markers which can be used as an option for treatment of cancers such as human breast cancer.